Lysosomal storage diseases. Sphingolipidoses — Fabry, Gaucher and Farber diseases

The epidemiology, clinical biochemical and molecular genetic characteristics of glycosphingolipidoses with impaired metabolism and excessive accumulation in parenchymal organs, bone and brain not only of sphingolipids, but also free cholesterol are presented. First of all, it is sphingomyelin lipidosis, or NiemannPick disease, a clinically polymorphic and genetically heterogeneous group of rare monogenic diseases. Types A and B, which differ in onset and severity, are allelic diseases and are caused by the presence of recessive mutations in the lysosomal acid sphingomyelinase (SMPD1) gene. Type A is a classic acute neuronopathy, which starts in 85% of cases before 6 months, death occurs before the age of 3 years. The cause of the disease is mutations with premature termination of translation or severe impairment of the catalytic activity of the enzyme. In type B, missense mutations are more common. This is a chronic visceral form, in which neurological symptoms are usually absent, and patients survive into adolescence. Juvenile and adult forms of chronic neuronopathy type C are genetically heterogeneous. In 95% of cases they are caused by mutations in the NPC1 gene (type C1) and in 5% in the NPC2 gene (type C2). The products of these genes are transmembrane proteins responsible for the transport of cholesterol and other lipids. Cholesterol ester storage disease, or Wolman disease, is caused by hereditary deficiency of lysosomal acid lipase A. The possibility of early diagnosis of these diseases based on neonatal screening is discussed in order to increase the effectiveness of their prevention and treatment. The importance of experimental models for studying the molecular basis of the pathogenesis of these severe hereditary diseases and developing various therapeutic approaches, such as bone marrow transplantation, enzyme replacement therapy, and substrate-reducing therapy, is emphasized. A clinical example of NiemannPick disease type C is presented.

Lysosomal storage diseases. Sphingolipidoses — sphingomyelin lipidosis, or Niemann–Pick disease, Wolman disease

Gorbunova

Бучинская²

2022

Lysosomal storage diseases. Sphingolipidoses — gangliosidoses

Gorbunova,

Buchinskaia,

Liazina

et al. 2023

Epidemiology, clinical, biochemical and molecular genetic characteristics of gangliosidoses, genetically heterogeneous group of autosomal recessive diseases caused by hereditary deficiency of lysosomal glycohydrolases involved in the catabolism of GM1-, GM2- and GA2-gangliosides, are presented. Three clinical forms of GM1 gangliosidosis are caused by hereditary deficiency of lysosomal β-galactosidase, one of the activities of which is the release of galactose from carbohydrate complexes. As a result, GM1-ganglioside and, to a lesser extent, keratan sulfate accumulate in the lysosomes of neurons and other cells. Three genetically heterogeneous forms of GM2-gangliosidosis are associated with dysfunction of hexosaminidase activity. Tay–Sachs disease, or GM2 ganglioside variant B, is caused by mutations in the hexosaminidase alpha chain HEXA gene. Sandhoff’s disease is associated with mutations in the HEXB gene for the hexosaminidase beta chain. In this case, there is a deficiency of the A and B components of the enzyme — the null variant of GM2 gangliosidosis. In variant AB, or juvenile GM2 gangliosidosis, all hexosaminidase components are present, but the activating factor is defective due to mutations in the GM2A gene. All types of gangliosidosis are characterized by progressive retardation of psychomotor development and early death of patients, most often under the age of 3 years. The frequency of various types of gangliosidoses in different populations does not exceed 1 : 300,000. An exception is the ethic group of Ashkenazi Jews, in which the incidence of Tay–Sachs disease, reaches 1 : 3000, which makes total screening of heterozygotes and prenatal diagnosis of the disease in high-risk families economically justified. The article highlights the importance of experimental models for studying the molecular basis of pathogenesis and developing various therapeutic approaches, such as bone marrow transplantation, enzyme replacement therapy and substrate reducing therapy, gene therapy, and genome editing. Clinical examples of patients with gangliosidosis are given to improve the efficiency of diagnostics of these rare diseases by clinicians.

Lysosomal storage diseases. Sphingolipidoses – leukodystrophy

Gorbunova,

Buchinskaia,

Vechkasova

et al. 2024

Epidemiological, clinical, biochemical and molecular-genetic characteristics of lysosomal leukodystrophies are presented, which include metachromatic leukodystrophy, globoid cell leukodystrophy, or Krabbe disease, combined saposin and multiple sulfatase deficiency. The pathogenesis of metachromatic and globoid cell leukodystrophy is based on hereditary deficiency of two lysosomal enzymes — arylsulfatase A and galactocerebrosidase, accompanied by excessive accumulation of galactosphingosulfatides and galactosylceramide, respectively. The consequence of this is demyelination of the central and peripheral nervous system and damage to the white matter of the brain. Experimental models show effectiveness of pathogenetic approaches, such as hematopoietic stem cell transplantation and gene therapy, only if treatment is started before the development of severe neurological anomalies. In this regard, neonatal screening methods for these two forms of leukodystrophy are being developed, which have been particularly successful in the early diagnosis of Krabbe disease. For each of the two leukodystrophies (metachromatic and globoid cell), rare genetic variants have been described due to the absence of activator proteins for arylsulfatase A and galactocerebrosidase (saposins B and C), respectively, due to specific mutations in the gene of the precursor of saposins, prosaposin (PSPA). Mutations in the PSPA gene resulting in the absence of all four saposins (A, D, C and D) are the cause of combined saposin deficiency, characterized by the development of severe neurological disorders soon after birth and death before the age of 1 year. The pathogenesis of multiple sulfatase deficiency is based on the accumulation of sulfatides, sulfated glycosaminoglycans, sphingolipids, and steroid sulfates, caused by inactivating mutations in the SUMF1 gene of the sulfatase-modifying factor 1 involved in the biosynthesis of all sulfatases. The disease is characterized by a combined manifestation of metachromatic leukodystrophy and mucopolysaccharidosis in combination with severe neurological disorders, mental retardation, sensorineural hearing loss and ichthyosis. Clinical guidelines for the diagnosis, management and therapy of combined saposin and multiple sulfatase deficiency have not yet been developed. The article presents a description of a clinical case of Krabbe disease in a child observed in the medical genetic center of St. Petersburg.